By Alexandra Demetriou

The National Science Foundation recently awarded an Emerging Frontiers in Research and Innovation (EFRI) grant of $1,999,999 to Mark Humayun, MD, PhD, director of the USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics and co-director of the USC Roski Eye Institute. The grant will support an innovative and multidisciplinary project combining engineering and molecular biology to slow down or potentially reverse retinal degeneration. The USC Ginsburg Institute researchers are investigating how electrical stimulation can be used to turn off genes that cause retinal disease while activating “neuroprotective” genes –– named for their abilities to promote healing in the retina, which is part of the central nervous system.

THE CONCEPT

The idea stemmed from a key observation Humayun and his colleagues made while examining patients with severe retinal degeneration who had received Argus II retinal implants, co-invented by Humayun. The Argus II system uses electrical stimulation to transmit visual information from a small camera mounted on the patient’s glasses to the retinal implant, allowing blind patients to regain some eyesight. In patients who received an implant in one eye, Humayun and his team noticed that the area of the retina surrounding the implant was healthier than areas further from the implant or compared to the same regions of the opposite eye. This led them to hypothesize that the electrical stimulation from the Argus prosthesis was somehow preserving neurons within the retina.

They attributed this phenomenon to epigenetic changes, or modifications that happen across the genome to change gene activity. To understand epigenetic changes, think of sports teams. Not all players need to be in the game at once, so the coach decides who plays and who sits on the bench. Similarly, humans have approximately 21,000 protein-coding genes at our disposal, and epigenetic changes act as genomic ‘coaches’ to regulate which genes are active and which sit out at a given time in one’s life. In the case of retinal degeneration, this epigenetic regulation gets thrown off, causing inactivation of genes beneficial to healthy cell function and activation of those that can lead to dysfunction and cell death. USC Ginsburg Institute scientists were among the first researchers to propose that electromagnetic stimulation could be used in patients to alter this epigenetic regulation in a way that helped promote retinal healing.

This ambitious goal would require a feat of bioengineering, combined with in-depth understanding of gene regulation. Humayun, an ophthalmologist and biomedical engineer, teamed up with electrical engineer Gianluca Lazzi, PhD, MBA, translational genomics expert Bodour Salhia, PhD, and a group of scientists at the Northwestern University Center for Physical Genomics and Engineering. Together, the multidisciplinary team is developing a non-invasive, wearable device to electrically stimulate the eye in a safe, controlled way to modify gene expression in the retina and slow or reverse degenerative disease.

TECHNICAL APPROACH

Humayun and Lazzi are working on developing what they call an “e-lens,” which generates electromagnetic fields and can be worn much like a contact lens throughout the night. Now, anyone with contacts has likely been told not to wear them to sleep, because the lenses prevent oxygen from reaching the cornea and, coupled with a closed eyelid, can cause damage due to oxygen deprivation. The e-lens avoids that issue because the team designed it in the shape of a ring that sits around the perimeter of the cornea rather than covering it, making the device safe to wear overnight. Electromagnetic fields from the e-lens would then transmit across the short distance from the cornea to the retina while patients sleep. The e-lens is still in development, but the researchers are working on refining the device and ideally creating inexpensive, single-use coils safe for regular use.

Meanwhile, Salhia is applying her translational genomics expertise to characterize the types of epigenetic changes that electromagnetic fields induce, while working on answering why these changes have a net positive effect on the retina. The team initially identified approximately 3,000 genes that appear to be activated or inactivated due to electrical stimulation, so the goal now is to figure out which of these epigenetic changes are most likely causing the neuroprotective effects.

Crucially, the team has to determine the ideal schedule for retinal stimulation in a theoretical patient. In preliminary studies, the team has identified three groups of genetic responses to stimulation that occur at different speeds: quick and transient genetic changes that show up immediately but are unnoticeable after a few days, quick and sustained changes, and delayed genetic changes. The research team at Northwestern is currently using a computer model of the retina to better track these changes both spatially and over time. Using this information, the team will determine the ideal frequency and duration of time that patients would need to wear the e-lens to benefit from long-lasting neuroprotection.

FUTURE IMPACT

Ideally, this non-invasive treatment could benefit patients with conditions such as retinitis pigmentosa (RP), primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). The technology could preemptively slow disease in early-stage patients, or it could serve as an adjunct treatment to complement drug or surgical interventions for patients with late-stage retinal degeneration.

Most cases of retinal degeneration aren’t due to just one defective gene, so the fact that this technique affects an entire gamut of genes and leads to coordinated activation of beneficial changes makes it especially promising. The researchers’ findings that electrical stimulation can inhibit cell death and promote healing likely have far-reaching potential to benefit patients with other neurodegenerative diseases and neural injuries like strokes or closed-head injuries.

“That’s the beauty of translational genomics –– it transcends disciplines. You can apply epigenomics and genomics technologies to any disease or system you want to study,” Salhia says. “It grows our world a little bit, because we have technology that we can share with others,” she continues, adding that these applications have a great deal of potential to impact human health moving forward.

“This is a very left field approach that is the result of the efforts of a highly interdisciplinary team of scientists working together,” Salhia continues, adding that one of the most rewarding parts of this project has been collaborating with researchers from widely different backgrounds and using the project as an opportunity to teach each other about their respective disciplines.

“It’s very sci-fi, and we’re really just starting at the beginning,” Salhia continues. “This is just the tip of the iceberg, and this grant is going to allow us to really expand our efforts.”